Advances in cytoreductive surgery and combination chemotherapy have improved 5-year survival in patients with epithelial ovarian cancer, but the rate of cure remains essentially unchanged over the last two decades. Computer models suggest that detection of ovarian cancer in early stage (I-II) could improve rates of cure by 10-30%. Sequential use of serum biomarkers measured over time followed by TVS in a small fraction of postmenopausal women with rising CA125 has proven more specific and more sensitive than either modality used alone. Using this strategy, the United Kingdom Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) and the Normal Risk Ovarian Cancer Screening Study (NROSS) in the United States have shown that only 3 operations are required to detect each case of ovarian cancer. Over the last 13 years, our group has conducted the NROSS study in 4,904 postmenopausal women at average risk for ovarian cancer. Annual determinations of CA125 have been analyzed by the Risk of Ovarian Cancer Algorithm (ROCA) developed by Dr. Skates. If the risk does not change, women return in a year; if it increases markedly, TVS is performed and participants are referred to a gynecologic oncologist; if the risk is intermediate CA125 is repeated in 3 months. Fifteen operations have been performed to detect 10 ovarian cancers. Two were borderline tumors and 8 were invasive with 8 of the 10 (80%) in Stage I or II. The NROSS trial has utilized a well-coordinated network of 7 sites in the United States where 22,981 blood samples have been obtained, processed and stored with standard operating protocols. Pre-operative specimens from MDACC have been banked from 502 women with ovarian cancer and 737 with benign disease. This has provided a valuable resource for evaluating new biomarkers. As CA125 is expressed by only 80% of epithelial ovarian cancers, additional biomarkers will be required to optimize sensitivity. Our group has found that HE4 and CA72.4 can detect 16% of the cases missed by CA125 in samples from the UKCTOCS trial. Autoantibodies to tumor associated antigens have shown even greater promise. Elevated levels of autoantibodies against TP53 have been found in 20-25% of patients with normal CA125 at the time of conventional diagnosis. Titers of anti-TP53 rise 13.5 months (mean) prior to CA125 and 33 months (mean) prior to diagnosis in patients who present without an increase in CA125. At present we are developing a new ROCA that incorporates CA125, HE4, CA72.4 and anti-TP53 autoantibody data. A multidisciplinary team of 27 investigators will pursue the following Specific Aims: 1) to conduct a screening trial to determine the specificity and positive predictive value for a 4 biomarker ROCA including CA125, HE4, CA72.4 and anti-TP53 autoantibodies in a two stage strategy for early detection of ovarian cancer in postmenopausal women at average risk for the disease; 2) to maintain and share a serum and plasma bank to facilitate evaluation of novel biomarkers for early detection; 3) to collaborate with other Centers in the EDRN to evaluate additional biomarkers for early detection of ovarian cancer.